US3354164A - S-triazolo-[3, 4-a] isoquinolines and process - Google Patents

S-triazolo-[3, 4-a] isoquinolines and process Download PDF

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Publication number
US3354164A
US3354164A US504093A US50409365A US3354164A US 3354164 A US3354164 A US 3354164A US 504093 A US504093 A US 504093A US 50409365 A US50409365 A US 50409365A US 3354164 A US3354164 A US 3354164A
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United States
Prior art keywords
triazolo
isoquinoline
isoquinolines
chloride
solution
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Expired - Lifetime
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US504093A
Inventor
John E Francis
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Novartis Corp
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Geigy Chemical Corp
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Priority to US504093A priority Critical patent/US3354164A/en
Application filed by Geigy Chemical Corp filed Critical Geigy Chemical Corp
Priority to AT984466A priority patent/AT263003B/en
Priority to FR81061A priority patent/FR1502974A/en
Priority to NL6614979A priority patent/NL6614979A/xx
Priority to BE688659D priority patent/BE688659A/xx
Priority to GB47225/66A priority patent/GB1116308A/en
Priority to CH1533266A priority patent/CH475998A/en
Priority to DK547366AA priority patent/DK119505B/en
Priority to DE19661695094 priority patent/DE1695094A1/en
Priority to IL26734A priority patent/IL26734A/en
Priority to NO165307A priority patent/NO119591B/no
Priority to ES0332645A priority patent/ES332645A1/en
Application granted granted Critical
Publication of US3354164A publication Critical patent/US3354164A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • R indicates hydrogen or alkyl
  • alkyl when used in the specification and appended claims is intended a branched or straight hydrocarbon chain.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondarybutyl, tertiary butyl, pentyl, isopentyl, hexyl and the like.
  • the compounds of the present invention are valuable cardiovascular agents, in particular, coronary dilating agents.
  • cardiovascular agents in particular, coronary dilating agents.
  • anesthetized dog arterial blood pressure is decreased, cardiac force is increased and coronary flow is increased after administration of 3- methyl-s-triazolo-[3,4-a] isoquinoline.
  • compositions may be administered parenterally or orally in any of the usual pharmaceutical forms including tablets, capsules, powders, suspensions, solutions, syrups and the like.
  • Particularly valuable formulations include sustained release preparations which may be compounded by any of the known procedures.
  • the therapeutically valuable compounds of the present invention include all physiologically acceptable acid addition salts and physiologically acceptable quaternary ammonium salts of the s-triazolo-[3,4-a] isoquinolines characterized by Formula I.
  • physiologically acceptable, non-toxic addition salts include those derived from organic and inorganic acids, such as, without limitation, hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, lactic, succinic, malic, maleic, aconitic, phthalic, tartaric and the like acids.
  • the new s-triazolo-[3,4-a] isoquinolines can be obtained by the following processes:
  • a process for the preparation of 3-methyl s-triazolo- [3,4-a] isoquinoline which comprises treating l-hydrazinoisoquinoline with hot acetic anhydride until cyclization is susbtantially completed and recovering said product.
  • the product may be obtained by reacting acetic anhydride or an acetyl halide and l-hydrazino isoquinoline with a tertiary base with or without an inert solvent until cyclization is substantially completed and recovering said product.
  • tertiary bases which may be used are pyridine, quinoline and trialkylamines such as triethylamine.
  • inert solvents which may be used are aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as tetrachloroethane and chlorobenzene and ethers such as diethyleneglycol dimethyl ether, dioxane and the like.
  • Also contemplated by this invention is a process for the preparation of s-triazolo-[3,4-,a] isoquinoline, which comprises treating l-hydrazinoisoquinoline with hot formic acid until cyclization is substantially completed and 'recovering said compound.
  • these reactions may be carried out to partial completion and the cyclization completed by heating the partially cyclized product with a dehydrating agent such as phosphorous oxychloride.
  • a dehydrating agent such as phosphorous oxychloride.
  • the first crop (4.3 g.), M.P. 170172 was collected and partial evaporation of the mother liquors yielded a second crop of material (2.5 g.).
  • the combined material was recrystallized from benzene-hexane, decolorizing charcoal being used and the pure product obtained in colorless plates, M.P. 170-172".
  • 3-ethyl-s-triazolo-[3,4-a] isoquinoline can be prepared in a similar manner by using propionic anhydride in place of acetic anhydride.
  • N t l wherein R is hydrogen or alkyl; non-toxic acid addition salts thereof and non-toxic quaternary ammonium salts thereof.
  • a process for the preparation of s-triazolo-[3,4-a] isoquinolines which comprises treating l-hydrazino isoquinoline with hot acetic anhydride or hot formic acid, until cyclization is substantially complete, and recovering said s-;riazolo-[3,4-a] isoquinoline.
  • a compound according to claim 1 which is s-triazolo-[3,4-a] isoquinoline.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Measurement Of Velocity Or Position Using Acoustic Or Ultrasonic Waves (AREA)

Description

United States Patent No Drawing. Filed Oct. 23, 1965, Ser. No. 504,093 4 Claims. (Cl. 260-488) ISOQUINOLINES This invention relates to novel nitrogen-containing organic compounds and to intermediates and processes for the preparation thereof. More particularly it is concerned with s-t-riazolo-[BA- 1a] isoquinolines.
The compounds of the present invention are characterized by the structure of the following Formula I:
wherein R indicates hydrogen or alkyl.
By the term alkyl when used in the specification and appended claims is intended a branched or straight hydrocarbon chain. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondarybutyl, tertiary butyl, pentyl, isopentyl, hexyl and the like.
The compounds of the present invention are valuable cardiovascular agents, in particular, coronary dilating agents. For example, in the anesthetized dog, arterial blood pressure is decreased, cardiac force is increased and coronary flow is increased after administration of 3- methyl-s-triazolo-[3,4-a] isoquinoline.
These compounds may be administered parenterally or orally in any of the usual pharmaceutical forms including tablets, capsules, powders, suspensions, solutions, syrups and the like. Particularly valuable formulations include sustained release preparations which may be compounded by any of the known procedures.
The therapeutically valuable compounds of the present invention include all physiologically acceptable acid addition salts and physiologically acceptable quaternary ammonium salts of the s-triazolo-[3,4-a] isoquinolines characterized by Formula I. Such physiologically acceptable, non-toxic addition salts include those derived from organic and inorganic acids, such as, without limitation, hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, lactic, succinic, malic, maleic, aconitic, phthalic, tartaric and the like acids.
The new s-triazolo-[3,4-a] isoquinolines can be obtained by the following processes:
Convenient and novel processes within the scope of this invention useful to prepare 3-methyl s-triazolo-[3,4-a] isoquinoline are, in essence:
A process for the preparation of 3-methyl s-triazolo- [3,4-a] isoquinoline which comprises treating l-hydrazinoisoquinoline with hot acetic anhydride until cyclization is susbtantially completed and recovering said product. Alternatively, the product may be obtained by reacting acetic anhydride or an acetyl halide and l-hydrazino isoquinoline with a tertiary base with or without an inert solvent until cyclization is substantially completed and recovering said product. Examples of the tertiary bases which may be used are pyridine, quinoline and trialkylamines such as triethylamine. Examples of inert solvents which may be used are aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as tetrachloroethane and chlorobenzene and ethers such as diethyleneglycol dimethyl ether, dioxane and the like.
1 Such as acetyl chloride.
Also contemplated by this invention is a process for the preparation of s-triazolo-[3,4-,a] isoquinoline, which comprises treating l-hydrazinoisoquinoline with hot formic acid until cyclization is substantially completed and 'recovering said compound.
Alternatively, these reactions may be carried out to partial completion and the cyclization completed by heating the partially cyclized product with a dehydrating agent such as phosphorous oxychloride.
The following examples serve to illustrate :the present invention without limiting the same thereto:
EXAMPLE I s-Triazolo-[3'4-a] isoquinoline A mixture of l-hydrazi-noisoquinoline (4.77 g.) in formic acid (20 ml.) was stirred at reflux temperature for one hour. The clear solution was evaporated to dryness in vacuo. The white solid residue was dissolved in very dilute sodium bicarbonate and treated with concentrated sodium bicarbonate solution until the pH of the solution was neutral. A white solid precipitated. The material was collected, dried and twice recrystallized from benzene. s-Triazolo-[3,4-a] isoquinoline was thus obtained in White crystals, M.P. 113-117.
EXAMPLE II s-Triazolo-[3,4-a] isoquinoline litethanesulfonate s-Triazolo-[3,4-a] isoquinoline (169 mg.) was dissolved in methanol (10 ml.) and treated with methanesulfonic acid (0.1 ml.). The solution was heated for ten minutes on a steam bath, cooled and treated with dry ether to incipient crystallization. The methanesulfonate salt (300 mg.) was obtained on cooling and filtration. It melted at 20l204 C.
EXAMPLE III s-Triazolo- [3,4-a] isoquinoline hydrochloride s-Triazolo-[3,4-a] isoquinoline (85 mg.) in absolute methanol (10 ml.) was treated with dry hydrogen chloride during cooling in an ice-bath. When the solution was saturated with hydrogen chloride, it was treated with dry ether. The hydrochloride precipitated in colorless crystals, M.P. 275278.
EXAMPLE IV 3-methyl-s-triaz0l0-[3,4a] isoquinoline To a solution of benzene ml.), pyridine (40 ml.) and acetic anhydride (24 ml.) was added under stirring l-hydrazino isoquinoline (8 g.). A fine, pale yellow precipitate formed. The mixture was heated under refl x under exclusion of moisture for six hours and a pale yellow solution resulted. Evaporation of the solvent in vacuo afforded a white crystalline mass, which was then boiled with water until no order of pyridine or acetic acid remained. The aqueous solution was evaporated to dryness in vacuo and the residue recrystallized from benzene. The first crop (4.3 g.), M.P. 170172 was collected and partial evaporation of the mother liquors yielded a second crop of material (2.5 g.). The combined material was recrystallized from benzene-hexane, decolorizing charcoal being used and the pure product obtained in colorless plates, M.P. 170-172".
Calcd C, 72.14; H, 4.95; N, 22.92. Found: C, 71.96; H, 5.10; N, 22.69.
3-ethyl-s-triazolo-[3,4-a] isoquinoline can be prepared in a similar manner by using propionic anhydride in place of acetic anhydride.
EXAMPLE V A mixture of l-hydrazino isoquinoline (1 g.), pyridine 10 ml.), acetyl chloride (5 ml.) and dry toluene (50 ml.)
were heated at reflux for 16 hours. The mixture was cooled, washed with sodium carbonate solution and evaporated to dryness in vacuo. The residue was boiled with water until no smell of pyridine remained and the aqueous solution then evaporated in vacuo. The residue was recrystallized from benzene-hexane with decolorizing charcoal and then twice more without charcoal and the colorless product, M.P. 170172, obtained.
When the acid halides shown in Column A are substituted for acetyl chloride, the R group in the product obtained is shown in Column B.
(A) Starting material: (B) R:
n-Butyryl chloride n-Propyl- Iso-butyryl chloride Iso-propyln-Valeryl chloride n-Butyl Iso-valeryl chloride Isobutyl n-Hexanoyl chloride n-Pentyl n-Heptanoyl chloride n-Hexyl Any changes in conditions such as temperature, pressure, reaction time and quantities used obvious to those skilled in the art are considered within the scope of this invention.
What is claimed is:
1. A compound selected from those of the formula:
N t l wherein R is hydrogen or alkyl; non-toxic acid addition salts thereof and non-toxic quaternary ammonium salts thereof.
2. 3-methyl-s-triazolo-[3,4-a] isoquinoline.
3. A process for the preparation of s-triazolo-[3,4-a] isoquinolines which comprises treating l-hydrazino isoquinoline with hot acetic anhydride or hot formic acid, until cyclization is substantially complete, and recovering said s-;riazolo-[3,4-a] isoquinoline.
4. A compound according to claim 1 which is s-triazolo-[3,4-a] isoquinoline.
References Cited UNITED STATES PATENTS 2,065,879 12/1936 Ach et a1. 260289 3,200,123 8/1965 Richardson et a1 260-288 ALEX MAZEL, Primary Examiner.
D. DAUS, Assistant Examiner.

Claims (1)

1. A COMPOUND SELECTED FRO THOSE OF THE FORMULA:
US504093A 1965-10-23 1965-10-23 S-triazolo-[3, 4-a] isoquinolines and process Expired - Lifetime US3354164A (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
US504093A US3354164A (en) 1965-10-23 1965-10-23 S-triazolo-[3, 4-a] isoquinolines and process
DE19661695094 DE1695094A1 (en) 1965-10-23 1966-10-21 Process for the preparation of new N-heterocycles
NL6614979A NL6614979A (en) 1965-10-23 1966-10-21
BE688659D BE688659A (en) 1965-10-23 1966-10-21
GB47225/66A GB1116308A (en) 1965-10-23 1966-10-21 Novels-triazolo[3,4-a]isoquinolines and the preparation thereof
CH1533266A CH475998A (en) 1965-10-23 1966-10-21 Process for the preparation of new s-triazolo (3,4-a) -isoquinolines
AT984466A AT263003B (en) 1965-10-23 1966-10-21 Process for the preparation of new s-triazolo [3,4-a] isoquinoline compounds and their salts
FR81061A FR1502974A (en) 1965-10-23 1966-10-21 Isoquinoline derivatives and their preparation
IL26734A IL26734A (en) 1965-10-23 1966-10-21 S-triazolo(3,4-a)isoquinoline derivatives and their preparation
DK547366AA DK119505B (en) 1965-10-23 1966-10-21 Analogous process for the preparation of s-triazolo [3,4-a] isoquinolines or acid addition salts thereof.
NO165307A NO119591B (en) 1965-10-23 1966-10-22
ES0332645A ES332645A1 (en) 1965-10-23 1966-10-22 Procedure for the preparation of new N-heterocicles. (Machine-translation by Google Translate, not legally binding)

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AT (1) AT263003B (en)
BE (1) BE688659A (en)
CH (1) CH475998A (en)
DE (1) DE1695094A1 (en)
DK (1) DK119505B (en)
ES (1) ES332645A1 (en)
FR (1) FR1502974A (en)
GB (1) GB1116308A (en)
IL (1) IL26734A (en)
NL (1) NL6614979A (en)
NO (1) NO119591B (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3454579A (en) * 1967-08-17 1969-07-08 American Cyanamid Co Imidazo(1,5-a)quinolin-1-one and thione derivatives
FR2135297A1 (en) * 1971-05-04 1972-12-15 Mallinckrodt Chemical Works Anti-inflammatory agents - contg s-triazolo 3,4-a)isoquinoline and derivs
US3873705A (en) * 1971-05-04 1975-03-25 Mallinckrodt Chemical Works Methods for reducing inflammatory reactions using certain s-triazolo-(3,4-a)-isoquinolines
USB426639I5 (en) * 1971-07-26 1976-02-03

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2065879A (en) * 1932-01-16 1936-12-29 C F Boehringer & Sochne G M B Derivatives of amino-quinolines and method of making same
US3200123A (en) * 1962-01-26 1965-08-10 Richardson Merreil Inc Imidazoquinolines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2065879A (en) * 1932-01-16 1936-12-29 C F Boehringer & Sochne G M B Derivatives of amino-quinolines and method of making same
US3200123A (en) * 1962-01-26 1965-08-10 Richardson Merreil Inc Imidazoquinolines

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3454579A (en) * 1967-08-17 1969-07-08 American Cyanamid Co Imidazo(1,5-a)quinolin-1-one and thione derivatives
FR2135297A1 (en) * 1971-05-04 1972-12-15 Mallinckrodt Chemical Works Anti-inflammatory agents - contg s-triazolo 3,4-a)isoquinoline and derivs
US3873705A (en) * 1971-05-04 1975-03-25 Mallinckrodt Chemical Works Methods for reducing inflammatory reactions using certain s-triazolo-(3,4-a)-isoquinolines
USB426639I5 (en) * 1971-07-26 1976-02-03
US3992539A (en) * 1971-07-26 1976-11-16 Mallinckrodt, Inc. S-triazolo-[3,4-a]isoquinolines in treating inflammatory disorders

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AT263003B (en) 1968-07-10
IL26734A (en) 1970-06-17
DK119505B (en) 1971-01-18
DE1695094A1 (en) 1970-12-10
BE688659A (en) 1967-04-21
CH475998A (en) 1969-07-31
ES332645A1 (en) 1967-07-16
FR1502974A (en) 1967-11-24
NO119591B (en) 1970-06-08
NL6614979A (en) 1967-04-24
GB1116308A (en) 1968-06-06

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